Publications by authors named "Christine Perret"

62 Publications

Notum Deacylates Octanoylated Ghrelin.

Mol Metab 2021 Feb 26:101201. Epub 2021 Feb 26.

Division of Structural Biology, Wellcome Centre for Human Genetics, Oxford University, Oxford, OX3 7BN, UK. Electronic address:

Objectives: The only proteins known to be modified by O-linked lipidation are Wnts and ghrelin, and enzymatic removal of this post-translational modification inhibits ligand activity. Indeed, the Wnt-deacylase activity of Notum is the basis of its ability to act as a feedback inhibitor of Wnt signalling. Whether Notum also deacylates ghrelin has not been determined.

Methods: We used mass-spectrometry to assay ghrelin deacylation by Notum and co-crystallisation to reveal enzyme-substrate interactions at the atomic level. CRISPR/Cas technology was used to tag endogenous Notum and assess its localisation in mice while liver-specific Notum knock-out mice allowed us to investigate the physiological role of Notum in modulating the level of ghrelin deacylation.

Results: Mass-spectrometry detected the removal of octanoyl from ghrelin by purified active Notum, but not by an inactive mutant. The 2.2 Å resolution crystal structure of the Notum-ghrelin complex shows the octanoyl lipid is accommodated in the hydrophobic pocket of Notum. The knock-in allele expressing HA-tagged Notum reveals that Notum is produced in the liver and present in the bloodstream, albeit at a low level. Liver-specific inactivation of Notum in animals fed with a high fat diet leads to a small but significant increase in acylated ghrelin in the circulation, while no such increase is seen in wildtype animals on the same diet.

Conclusions: Overall our data demonstrate Notum can act as a ghrelin deacylase, and that this may be physiologically relevant under high fat diet conditions. Our work therefore adds Notum to the list of enzymes, including butylcholineasterase and other carboxylesterases, that modulate the acylation state of ghrelin. The contribution of multiple enzymes could help tune the activity of this important hormone to a wide range of physiological conditions.
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http://dx.doi.org/10.1016/j.molmet.2021.101201DOI Listing
February 2021

Lkb1 suppresses amino acid-driven gluconeogenesis in the liver.

Nat Commun 2020 11 30;11(1):6127. Epub 2020 Nov 30.

Université de Paris, Institut Cochin, INSERM, CNRS, F75014, Paris, France.

Excessive glucose production by the liver is a key factor in the hyperglycemia observed in type 2 diabetes mellitus (T2DM). Here, we highlight a novel role of liver kinase B1 (Lkb1) in this regulation. We show that mice with a hepatocyte-specific deletion of Lkb1 have higher levels of hepatic amino acid catabolism, driving gluconeogenesis. This effect is observed during both fasting and the postprandial period, identifying Lkb1 as a critical suppressor of postprandial hepatic gluconeogenesis. Hepatic Lkb1 deletion is associated with major changes in whole-body metabolism, leading to a lower lean body mass and, in the longer term, sarcopenia and cachexia, as a consequence of the diversion of amino acids to liver metabolism at the expense of muscle. Using genetic, proteomic and pharmacological approaches, we identify the aminotransferases and specifically Agxt as effectors of the suppressor function of Lkb1 in amino acid-driven gluconeogenesis.
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http://dx.doi.org/10.1038/s41467-020-19490-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705018PMC
November 2020

Essential role for autophagy protein ATG7 in the maintenance of intestinal stem cell integrity.

Proc Natl Acad Sci U S A 2020 05 5;117(20):11136-11146. Epub 2020 May 5.

Université de Paris, Institut Cochin, INSERM, U1016, CNRS UMR8104, F-75014 Paris, France

The intestinal epithelium acts as a barrier between the organism and its microenvironment, including the gut microbiota. It is the most rapidly regenerating tissue in the human body thanks to a pool of intestinal stem cells (ISCs) expressing The intestinal epithelium has to cope with continuous stress linked to its digestive and barrier functions. Epithelial repair is crucial to maintain its integrity, and Lgr5-positive intestinal stem cell (Lgr5ISC) resilience following cytotoxic stresses is central to this repair stage. We show here that autophagy, a pathway allowing the lysosomal degradation of intracellular components, plays a crucial role in the maintenance and genetic integrity of Lgr5ISC under physiological and stress conditions. Using conditional mice models lacking the autophagy gene specifically in all intestinal epithelial cells or in Lgr5ISC, we show that loss of Atg7 induces the p53-mediated apoptosis of Lgr5ISC. Mechanistically, this is due to increasing oxidative stress, alterations to interactions with the microbiota, and defective DNA repair. Following irradiation, we show that Lgr5ISC repair DNA damage more efficiently than their progenitors and that this protection is Atg7 dependent. Accordingly, we found that the stimulation of autophagy on fasting protects Lgr5ISC against DNA damage and cell death mediated by oxaliplatin and doxorubicin treatments. Finally, deletion prevents the death of -deficient Lgr5ISC but promotes genetic instability and tumor formation. Altogether, our findings provide insights into the mechanisms underlying maintenance and integrity of ISC and highlight the key functions of Atg7 and p53.
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http://dx.doi.org/10.1073/pnas.1917174117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245075PMC
May 2020

Proteome analysis of formalin-fixed paraffin-embedded colorectal adenomas reveals the heterogeneous nature of traditional serrated adenomas compared to other colorectal adenomas.

J Pathol 2020 03 15;250(3):251-261. Epub 2019 Dec 15.

Department of Pathology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris Centre, Hôpital Cochin Department, Paris, France.

Traditional serrated adenoma (TSA) remains the least understood of all the colorectal adenomas, although these lesions have been associated with a significant cancer risk, twice that of the conventional adenoma (CAD) and of the sessile serrated adenoma (SSA/P). This study was performed to investigate the proteomic profiles of the different colorectal adenomas to better understand the pathogenesis of TSA. We performed a global quantitative proteome analysis using the label-free quantification (LFQ) method on 44 colorectal adenoma (12 TSAs, 15 CADs, and 17 SSA/Ps) and 17 normal colonic mucosa samples, archived as formalin-fixed paraffin-embedded blocks. Unsupervised consensus hierarchical clustering applied to the whole proteomic profile of the 44 colorectal adenomas identified four subtypes: C1 and C2 were well-individualized clusters composed of all the CADs (15/15) and most of the SSA/Ps (13/17), respectively. This is consistent with the fact that CADs and SSA/Ps are homogeneous and distinct colorectal adenoma entities. In contrast, TSAs were subdivided into C3 and C4 clusters, consistent with the more heterogeneous entity of TSA at the morphologic and molecular levels. Comparison of the proteome expression profile between the adenoma subtypes and normal colonic mucosa further confirmed the heterogeneous nature of TSAs, which overlapped either on CADs or SSA/Ps, whereas CADs and SSAs formed homogeneous and distinct entities. Furthermore, we identified LEFTY1 a new potential marker for TSAs that may be relevant for the pathogenesis of TSA. LEFTY1 is an inhibitor of the Nodal/TGFβ pathway, which we found to be one of the most overexpressed proteins specifically in TSAs. This finding was confirmed by immunohistochemistry. Our study confirms that CADs and SSA/Ps form homogeneous and distinct colorectal adenoma entities, whereas TSAs are a heterogeneous entity and may arise from either SSA/Ps or from normal mucosa evolving through a process related to the CAD pathway. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5366DOI Listing
March 2020

Osteoblast-derived NOTUM reduces cortical bone mass in mice and the locus is associated with bone mineral density in humans.

FASEB J 2019 10 15;33(10):11163-11179. Epub 2019 Jul 15.

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Osteoporosis is a common skeletal disease, affecting millions of individuals worldwide. Currently used osteoporosis treatments substantially reduce vertebral fracture risk, whereas nonvertebral fracture risk, mainly caused by reduced cortical bone mass, has only moderately been improved by the osteoporosis drugs used, defining an unmet medical need. Because several wingless-type MMTV integration site family members (WNTs) and modulators of WNT activity are major regulators of bone mass, we hypothesized that NOTUM, a secreted WNT lipase, might modulate bone mass an inhibition of WNT activity. To characterize the possible role of endogenous NOTUM as a physiologic modulator of bone mass, we developed global, cell-specific, and inducible -inactivated mouse models. expression was high in the cortical bone in mice, and conditional inactivation revealed that osteoblast lineage cells are the principal source of NOTUM in the cortical bone. Osteoblast lineage-specific inactivation increased cortical bone thickness an increased periosteal circumference. Inducible inactivation in adult mice increased cortical bone thickness as a result of increased periosteal bone formation, and silencing of expression in cultured osteoblasts enhanced osteoblast differentiation. Large-scale human genetic analyses identified genetic variants mapping to the locus that are strongly associated with bone mineral density (BMD) as estimated with quantitative ultrasound in the heel. Thus, osteoblast-derived NOTUM is an essential local physiologic regulator of cortical bone mass effects on periosteal bone formation in adult mice, and genetic variants in the locus are associated with BMD variation in adult humans. Therapies targeting osteoblast-derived NOTUM may prevent nonvertebral fractures.-Movérare-Skrtic, S., Nilsson, K. H., Henning, P., Funck-Brentano, T., Nethander, M., Rivadeneira, F., Coletto Nunes, G., Koskela, A., Tuukkanen, J., Tuckermann, J., Perret, C., Souza, P. P. C., Lerner, U. H., Ohlsson, C. Osteoblast-derived NOTUM reduces cortical bone mass in mice and the locus is associated with bone mineral density in humans.
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http://dx.doi.org/10.1096/fj.201900707RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766646PMC
October 2019

Mammalian Target of Rapamycin Inhibitors, New Drugs for Beta-Catenin-Mutated Hepatocellular Carcinomas?

Hepatology 2019 10 16;70(4):1473-1476. Epub 2019 May 16.

Université Grenoble Alpes, Grenoble, France.

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http://dx.doi.org/10.1002/hep.30768DOI Listing
October 2019

Letter to the Editor: Comment on Qiao et al.

Hepatology 2019 08;70(2):763-764

Institut Cochin, Paris Descartes University, Paris, France.

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http://dx.doi.org/10.1002/hep.30650DOI Listing
August 2019

The concomitant loss of APC and HNF4α in adult hepatocytes does not contribute to hepatocarcinogenesis driven by β-catenin activation.

Liver Int 2019 04 24;39(4):727-739. Epub 2019 Feb 24.

Inserm, U1016, Institut Cochin, Paris, France.

Background & Aims: Loss of hepatocyte nuclear factor-4α (HNF4α), a critical factor driving liver development and differentiation, is frequently associated with hepatocellular carcinoma (HCC). Our recent data revealed that HNF4α level was decreased in mouse and human HCCs with activated β-catenin signalling. In addition, increasing HNF4α level by miR-34a inhibition slowed tumour progression of β-catenin-activated HCC in mice.

Methods: We generated a Hnf4a Apc /TTR-Cre (Hnf4a/Apc ) mouse line and evaluated the impact of Hnf4a disruption on HCC development and liver homoeostasis.

Results: There was no significant impact of Hnf4a disruption on tumour onset and progression in Apc model. However, we observed an unexpected phenotype in 28% of Hnf4a mice maintained in a conventional animal facility, which presented disorganized portal triads, characterized by stenosis of the portal vein and increased number and size of hepatic arteries and bile ducts. These abnormal portal structures resemble the human idiopathic non-cirrhotic portal hypertension syndrome. We correlated the presence of portal remodelling with a higher expression of protein and mRNA levels of TGFβ and BMP7, a key regulator of the TGFβ-dependent endothelial-to-mesenchymal transition.

Conclusion: These data demonstrate that HNF4α does not play a major role during β-catenin-driven HCC, thus revealing that the tumour suppressor role of HNF4α is far more complex and dependent probably on its temporal expression and tumour context. However, HNF4α loss in adult hepatocytes could induce abnormal portal structures resembling the human idiopathic non-cirrhotic portal hypertension syndrome, which may result from endothelial- and epithelial-to-mesenchymal transitions.
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http://dx.doi.org/10.1111/liv.14068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387933PMC
April 2019

LKB1 signaling is activated in CTNNB1-mutated HCC and positively regulates β-catenin-dependent CTNNB1-mutated HCC.

J Pathol 2019 04 27;247(4):435-443. Epub 2018 Dec 27.

Development Reproduction Cancer, INSERM, U1016, Institut Cochin, Paris, France.

Hepatocellular carcinomas (HCCs) are known to be highly heterogenous. Within the extensive histopathological and molecular heterogeneity of HCC, tumors with mutations in CTNNB1, encoding β-catenin (CTNNB1-mutated HCC), constitute a very homogeneous group. We previously characterized a distinctive metabolic and histological phenotype for CTNNB1-mutated HCC. They were found to be well-differentiated, almost never steatotic, and often cholestatic, with a microtrabecular or acinar growth pattern. Here, we investigated whether LKB1, which controls energy metabolism, cell polarity, and cell growth, mediates the specific phenotype of CTNNB1-mutated HCC. The LKB1 protein was overexpressed in CTNNB1-mutated HCC and oncogenic activation of β-catenin in human HCC cells induced the post-transcriptional accumulation of the LKB1 protein encoded by the LKB1 (STK11) gene. Hierarchical clustering, based on the expression of a murine hepatic liver Lkb1 (Stk11) signature in a human public dataset, identified a HCC cluster, composed of almost all the CTNNB1-mutated HCC, that expresses a hepatic liver LKB1 program. This was confirmed by RT-qPCR of an independent cohort of CTNNB1-mutated HCC and the suppression of the LKB1-related profile upon β-catenin silencing of CTNNB1-mutated human hepatoma cell lines. Previous studies described an epistatic relationship between LKB1 and CTNNB1 in which LKB1 acts upstream of CTNNB1. Thus, we also analyzed the consequences of Lkb1 deletion on the zonation of hepatic metabolism, known to be the hallmark of β-catenin signaling in the liver. Lkb1 was required for the establishment of metabolic zonation in the mouse liver by positively modulating β-catenin signaling. We identified positive reciprocal cross talk between the canonical Wnt pathway and LKB1, both in normal liver physiology and during tumorigenesis that likely participates in the amplification of the β-catenin signaling by LKB1 and the distinctive phenotype of the CTNNB1-mutated HCC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5202DOI Listing
April 2019

β-catenin-activated hepatocellular carcinomas are addicted to fatty acids.

Gut 2019 02 12;68(2):322-334. Epub 2018 Apr 12.

INSERM, U1016, Institut Cochin, Paris, France.

Objectives: -mutated hepatocellular carcinomas (HCCs) constitute a major part of human HCC and are largely inaccessible to target therapy. Yet, little is known about the metabolic reprogramming induced by β-catenin oncogenic activation in the liver. We aimed to decipher such reprogramming and assess whether it may represent a new avenue for targeted therapy of -mutated HCC.

Design: We used mice with hepatocyte-specific oncogenic activation of β-catenin to evaluate metabolic reprogramming using metabolic fluxes on tumourous explants and primary hepatocytes. We assess the role of in knock-out mice and analysed the consequences of fatty acid oxidation (FAO) using etomoxir. We explored the expression of the FAO pathway in an annotated human HCC dataset.

Results: β-catenin-activated HCC were not glycolytic but intensively oxidised fatty acids. We found that is a β-catenin target involved in FAO metabolic reprograming. Deletion of was sufficient to block the initiation and progression of β-catenin-dependent HCC development. FAO was also enriched in human -mutated HCC, under the control of the transcription factor PPARα.

Conclusions: FAO induced by β-catenin oncogenic activation in the liver is the driving force of the β-catenin-induced HCC. Inhibiting FAO by genetic and pharmacological approaches blocks HCC development, showing that inhibition of FAO is a suitable therapeutic approach for -mutated HCC.
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http://dx.doi.org/10.1136/gutjnl-2017-315448DOI Listing
February 2019

AXIN deficiency in human and mouse hepatocytes induces hepatocellular carcinoma in the absence of β-catenin activation.

J Hepatol 2018 06 7;68(6):1203-1213. Epub 2018 Mar 7.

INSERM, U1016, Institut Cochin, F-75014 Paris, France; CNRS, UMR8104, F-75014 Paris, France; Université Paris Descartes, F-75014 Paris, France; Equipe labellisée LNCC, France; Centre de Recherche sur l'Inflammation-Inserm UMR 1149-Université Paris Diderot, Paris, France. Electronic address:

Background & Aims: The Wnt/β-catenin pathway is the most frequently deregulated pathway in hepatocellular carcinoma (HCC). Inactivating mutations of the gene encoding AXIN1, a known negative regulator of the Wnt/β-catenin signaling pathway, are observed in about 10% of HCCs. Whole-genome studies usually place HCC with AXIN1 mutations and CTNNB1 mutations in the group of tumors with Wnt/β-catenin activated program. However, it has been shown that HCCs with activating CTNNB1 mutations form a group of HCCs, with a different histology, prognosis and genomic signature to those with inactivating biallelic AXIN1 mutations. We aimed to elucidate the relationship between CTNNB1 mutations, AXIN1 mutations and the activation level of the Wnt/β-catenin program.

Methods: We evaluated two independent human HCC datasets for the expression of a 23-β-catenin target genes program. We modeled Axin1 loss of function tumorigenesis in two engineered mouse models and performed gene expression profiling.

Results: Based on gene expression, we defined three levels of β-catenin program activation: strong, weak or no activation. While more than 80% CTNNB1-mutated tumors were found in the strong or in the weak activation program, most of the AXIN1-mutated tumors (>70%) were found in the subgroup with no activation. We validated this result by demonstrating that mice with a hepatocyte specific AXIN1 deletion developed HCC in the absence of β-catenin induction. We defined a 329-gene signature common in human and mouse AXIN1 mutated HCC that is highly enriched in Notch and YAP oncogenic signatures.

Conclusions: AXIN1-mutated HCCs occur independently of the Wnt/β-catenin pathway and involve Notch and YAP pathways. These pathways constitute potentially interesting targets for the treatment of HCC caused by AXIN1 mutations.

Lay Summary: Liver cancer has a poor prognosis. Defining the molecular pathways involved is important for developing new therapeutic approaches. The Wnt/β-catenin pathway is the most frequently deregulated pathway in hepatocellular carcinoma (HCC). Mutations of AXIN1, a member of this pathway, represent about 10% of HCC mutations. Using both human HCC collections and engineered mouse models of liver cancers with AXIN1 mutation or deletion, we defined a common signature of liver tumors mutated for AXIN1 and demonstrate that these tumors occur independently of the activation of the Wnt/β-catenin pathway.
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http://dx.doi.org/10.1016/j.jhep.2017.12.018DOI Listing
June 2018

LKB1 as a Gatekeeper of Hepatocyte Proliferation and Genomic Integrity during Liver Regeneration.

Cell Rep 2018 02;22(8):1994-2005

INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address:

Liver kinase B1 (LKB1) is involved in several biological processes and is a key regulator of hepatic metabolism and polarity. Here, we demonstrate that the master kinase LKB1 plays a dual role in liver regeneration, independently of its major target, AMP-activated protein kinase (AMPK). We found that the loss of hepatic Lkb1 expression promoted hepatocyte proliferation acceleration independently of metabolic/energetic balance. LKB1 regulates G/G progression, specifically by controlling epidermal growth factor receptor (EGFR) signaling. Furthermore, later in regeneration, LKB1 controls mitotic fidelity. The deletion of Lkb1 results in major alterations to mitotic spindle formation along the polarity axis. Thus, LKB1 deficiency alters ploidy profile at late stages of regeneration. Our findings highlight the dual role of LKB1 in liver regeneration, as a guardian of hepatocyte proliferation and genomic integrity.
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http://dx.doi.org/10.1016/j.celrep.2018.01.086DOI Listing
February 2018

Human hepatocellular carcinomas with a periportal phenotype have the lowest potential for early recurrence after curative resection.

Hepatology 2017 11 26;66(5):1502-1518. Epub 2017 Sep 26.

INSERM, INRA, Univ Rennes, CHU Rennes, Nutrition Metabolisms and Cancer (NuMeCan), CRB-Santé, Biosit, Biogenouest, UBL, Rennes, France.

Hepatocellular carcinomas (HCCs) exhibit a diversity of molecular phenotypes, raising major challenges in clinical management. HCCs detected by surveillance programs at an early stage are candidates for potentially curative therapies (local ablation, resection, or transplantation). In the long term, transplantation provides the lowest recurrence rates. Treatment allocation is based on tumor number, size, vascular invasion, performance status, functional liver reserve, and the prediction of early (<2 years) recurrence, which reflects the intrinsic aggressiveness of the tumor. Well-differentiated, potentially low-aggressiveness tumors form the heterogeneous molecular class of nonproliferative HCCs, characterized by an approximate 50% β-catenin mutation rate. To define the clinical, pathological, and molecular features and the outcome of nonproliferative HCCs, we constructed a 1,133-HCC transcriptomic metadata set and validated findings in a publically available 210-HCC RNA sequencing set. We show that nonproliferative HCCs preserve the zonation program that distributes metabolic functions along the portocentral axis in normal liver. More precisely, we identified two well-differentiated, nonproliferation subclasses, namely periportal-type (wild-type β-catenin) and perivenous-type (mutant β-catenin), which expressed negatively correlated gene networks. The new periportal-type subclass represented 29% of all HCCs; expressed a hepatocyte nuclear factor 4A-driven gene network, which was down-regulated in mouse hepatocyte nuclear factor 4A knockout mice; were early-stage tumors by Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program, and tumor-node-metastasis staging systems; had no macrovascular invasion; and showed the lowest metastasis-specific gene expression levels and TP53 mutation rates. Also, we identified an eight-gene periportal-type HCC signature, which was independently associated with the highest 2-year recurrence-free survival by multivariate analyses in two independent cohorts of 247 and 210 patients.

Conclusion: Well-differentiated HCCs display mutually exclusive periportal or perivenous zonation programs. Among all HCCs, periportal-type tumors have the lowest intrinsic potential for early recurrence after curative resection. (Hepatology 2017;66:1502-1518).
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http://dx.doi.org/10.1002/hep.29254DOI Listing
November 2017

De novo HAPLN1 expression hallmarks Wnt-induced stem cell and fibrogenic networks leading to aggressive human hepatocellular carcinomas.

Oncotarget 2016 Jun;7(26):39026-39043

Inserm, UMR991, Liver Metabolisms and Cancer, Rennes, France.

About 20% hepatocellular carcinomas (HCCs) display wild-type β-catenin, enhanced Wnt signaling, hepatocyte dedifferentiation and bad outcome, suggesting a specific impact of Wnt signals on HCC stem/progenitor cells. To study Wnt-specific molecular pathways, cell fates and clinical outcome, we fine-tuned Wnt/β-catenin signaling in liver progenitor cells, using the prototypical Wnt ligand Wnt3a. Cell biology assays and transcriptomic profiling were performed in HepaRG hepatic progenitors exposed to Wnt3a after β-catenin knockdown or Wnt inhibition with FZD8_CRD. Gene expression network, molecular pathology and survival analyses were performed on HCCs and matching non-tumor livers from 70 patients by real-time PCR and tissue micro-array-based immunohistochemistry. Wnt3a reprogrammed liver progenitors to replicating fibrogenic myofibroblast-like cells displaying stem and invasive features. Invasion was inhibited by 30 nM FZD7 and FZD8 CRDs. Translation of these data to human HCCs revealed two tight gene networks associating cell surface Wnt signaling, stem/progenitor markers and mesenchymal commitment. Both networks were linked by Hyaluronan And Proteoglycan Link Protein 1 (HAPLN1), that appeared de novo in aggressive HCCs expressing cytoplasmic β-catenin and stem cell markers. HAPLN1 was independently associated with bad overall and disease-free outcome. In vitro, HAPLN1 was expressed de novo in EPCAM¯/NCAM+ mesoderm-committed progenitors, upon spontaneous epithelial-mesenchymal transition and de-differentiation of hepatocyte-like cells to liver progenitors. In these cells, HAPLN1 knockdown downregulated key markers of mesenchymal cells, such as Snail, LGR5, collagen IV and α-SMA. In conclusion, HAPLN1 reflects a signaling network leading to stemness, mesenchymal commitment and HCC progression.
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http://dx.doi.org/10.18632/oncotarget.9346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5129911PMC
June 2016

"Fibrous nests" in human hepatocellular carcinoma express a Wnt-induced gene signature associated with poor clinical outcome.

Int J Biochem Cell Biol 2016 12 18;81(Pt A):195-207. Epub 2016 Aug 18.

Inserm, UMR991, Liver Metabolisms and Cancer, Rennes, France; Université de Rennes 1, F-35043 Rennes, France. Electronic address:

Hepatocellular carcinoma (HCC) is the 3rd cause of cancer-related death worldwide. Most cases arise in a background of chronic inflammation, extracellular matrix (ECM) remodeling, severe fibrosis and stem/progenitor cell amplification. Although HCCs are soft cellular tumors, they may contain fibrous nests within the tumor mass. Thus, the aim of this study was to explore cancer cell phenotypes in fibrous nests. Combined anatomic pathology, tissue microarray and real-time PCR analyses revealed that HCCs (n=82) containing fibrous nests were poorly differentiated, expressed Wnt pathway components and target genes, as well as markers of stem/progenitor cells, such as CD44, LGR5 and SOX9. Consistently, in severe liver fibroses (n=66) and in HCCs containing fibrous nests, weighted correlation analysis revealed a gene network including the myofibroblast marker ACTA2, the basement membrane components COL4A1 and LAMC1, the Wnt pathway members FZD1; FZD7; WNT2; LEF1; DKK1 and the Secreted Frizzled Related Proteins (SFRPs) 1; 2 and 5. Moreover, unbiased random survival forest analysis of a transcriptomic dataset of 247 HCC patients revealed high DKK1, COL4A1, SFRP1 and LAMC1 to be associated with advanced tumor staging as well as with bad overall and disease-free survival. In vitro, these genes were upregulated in liver cancer stem/progenitor cells upon Wnt-induced mesenchymal commitment and myofibroblast differentiation. In conclusion, fibrous nests express Wnt target genes, as well as markers of cancer stem cells and mesenchymal commitment. Fibrous nests embody the specific microenvironment of the cancer stem cell niche and can be detected by routine anatomic pathology analyses.
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http://dx.doi.org/10.1016/j.biocel.2016.08.017DOI Listing
December 2016

Dietary Methyl Donor Depletion Suppresses Intestinal Adenoma Development.

Cancer Prev Res (Phila) 2016 Oct 16;9(10):812-820. Epub 2016 Aug 16.

Center for Molecular Medicine, Neag Comprehensive Cancer Center, School of Medicine, UConn Health, Farmington, Connecticut.

The role of folate one-carbon metabolism in colorectal cancer development is controversial, with nutritional intervention studies producing conflicting results. It has been reported that Apc mice maintained on a diet deficient in the methyl donors folic acid, methionine, choline, and vitamin B12, and supplemented with homocysteine, show a greater than 95% reduction in intestinal tumor development. The present study extends these findings and shows that tumor protection afforded by dietary methyl donor deficiency (MDD) is long-lasting. After 11 weeks of MDD, tumor protection persisted for at least an additional 7 weeks of methyl donor repletion (22.2 ± 3.5 vs. 70.2 ± 4.6 tumors per mouse; P < 0.01). Sustained tumor protection was associated with a reduction in intestinal crypt length (26%, P < 0.01), crypt cell division and crypt fission, and an increase in apoptosis of both normal crypts and tumors (4.9- and 3.2-fold, respectively, P < 0.01). MDD also caused a significant reduction in the number of Dclk1-positive cells in the intestine (62%, P < 0.01), a long-lived crypt cell with cancer stem cell potential. Several undesirable effects associated with methyl donor restriction (e.g., reduced body weight gain) were shown to be transient and readily reversible following methyl donor repletion. Taken together, these results indicate that even temporary dietary methyl donor restriction in adenoma-prone mice can induce persistent changes to the intestinal epithelium and provide long-lasting tumor protection. These data also suggest that transient reductions in dietary methyl donor consumption should be considered when studying the impact of folate on colon cancer risk in humans. Cancer Prev Res; 9(10); 812-20. ©2016 AACR.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053888PMC
http://dx.doi.org/10.1158/1940-6207.CAPR-16-0042DOI Listing
October 2016

Generation of Mice with Hepatocyte-Specific Conditional Deletion of Notum.

PLoS One 2016 14;11(3):e0150997. Epub 2016 Mar 14.

Inserm, U1016, Institut Cochin, 75014 Paris, France.

Background: Fine tuning of the Wnt/β-catenin signaling pathway is essential for the proper development and function of the liver. Aberrant activation of this pathway is observed in 20%-40% of hepatocellular carcinomas (HCC). Notum encodes a secreted Wnt deacylase that inhibits Wnt activity and thereby restricts the zone of activation of Wnt/β-catenin signaling. An important role of NOTUM has been described in development in drosophila, planaria and zebrafish, but its role in the mammalian liver is unknown. Notum is required for spatial control of the Wnt/β-catenin signaling in several animal models and the Wnt/β-catenin pathway contributes to liver patterning involved in metabolic zonation. Therefore, Notum may be involved in the liver patterning induced by the Wnt/β-catenin signaling during the adult stage.

Methodology/principal Findings: We generated a conditional Notum knockout mouse mutant to study the effect of the deletion of Notum in the liver. We show that Notum is a direct target of the Wnt/β-catenin signaling in the liver. Liver-specific deletion of Notum did not modify liver zonation, but Notum deletion had a long-term effect on mouse physiology. In particular, male mutant mice developed metabolic disorders.

Conclusion: We show that Notum is not a key actor of Wnt/β-catenin-dependent liver patterning of adult mice, but has role in liver glucose homeostasis. Male mice deficient in Notum specifically in the liver develop metabolic dysfunctions implicating Notum in the development of Type 2 diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150997PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790944PMC
August 2016

A kinome siRNA screen identifies HGS as a potential target for liver cancers with oncogenic mutations in CTNNB1.

BMC Cancer 2015 Dec 29;15:1020. Epub 2015 Dec 29.

Department Development, Reproduction and Cancer, INSERM U1016, Institut Cochin, 24, rue du Faubourg Saint-Jacques, 75014, Paris, France.

Background: Aberrant activation of the Wnt/β-catenin pathway is a major and frequent event in liver cancer, but inhibition of oncogenic β-catenin signaling has proven challenging. The identification of genes that are synthetically lethal in β-catenin-activated cancer cells would provide new targets for therapeutic drug design.

Methods: We transfected the parental HuH6 hepatoblastoma cell line with a doxycycline-inducible shRNA against CTNNB1 (gene coding for β-catenin) to obtain an isogenic cell line pair with or without aberrant β-catenin signaling. Using this hepatoblastoma isogenic cell line pair, we performed a human kinome-wide siRNA screen to identify synthetic lethal interactions with oncogenic CTNNB1. The phenotypic readouts of the screen were cell proliferation, cell cycle arrest and apoptosis, which were assessed by image-based analysis. In addition, apoptosis was assessed by flow cytometric experiments and immunoblotting. The potential synthetic lethal relationship between candidates genes identified in the screen and oncogenic CTNNB1 was also investigated in a different cellular context, a colorectal HCT116 isogenic cell line pair.

Results: We first determined the experimental conditions that led to the efficient expression of shRNA against CTNNB1 and maximal reduction of β-catenin signaling activity in response to doxycycline treatment. Following high throughput screening in which 687 genes coding for kinases and proteins related to kinases (such as pseudokinases and phosphatases) were targeted, we identified 52 genes required for HuH6 survival. The silencing of five of these genes selectively impaired the viability of HuH6 cells with high β-catenin signaling: HGS, STRADA, FES, BRAF and PKMYT1. Among these candidates, HGS depletion had the strongest inhibitory effect on cell growth and led to apoptosis specifically in HuH6 with high β-catenin activity, while HuH6 with low β-catenin activity were spared. In addition, HGS was identified as a potential synthetic lethal partner of oncogenic CTNNB1 in the HCT116 colorectal isogenic cell line pair.

Conclusions: These results demonstrate the existence of crosstalk between β-catenin signaling and HGS. Importantly, HGS depletion specifically affected cells with uncontrolled β-catenin signaling activity in two different types of cancer (Hepatoblastoma HuH6 and colorectal HCT116), and thus may represent a new potential target for novel therapeutic strategies in liver and colorectal cancer.
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http://dx.doi.org/10.1186/s12885-015-2037-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696130PMC
December 2015

LKB1 and Notch Pathways Interact and Control Biliary Morphogenesis.

PLoS One 2015 21;10(12):e0145400. Epub 2015 Dec 21.

INSERM, U1016, Institut Cochin, F-75014 Paris, France.

Background: LKB1 is an evolutionary conserved kinase implicated in a wide range of cellular functions including inhibition of cell proliferation, regulation of cell polarity and metabolism. When Lkb1 is inactivated in the liver, glucose homeostasis is perturbed, cellular polarity is affected and cholestasis develops. Cholestasis occurs as a result from deficient bile duct development, yet how LKB1 impacts on biliary morphogenesis is unknown.

Methodology/principal Findings: We characterized the phenotype of mice in which deletion of the Lkb1 gene has been specifically targeted to the hepatoblasts. Our results confirmed that lack of LKB1 in the liver results in bile duct paucity leading to cholestasis. Immunostaining analysis at a prenatal stage showed that LKB1 is not required for differentiation of hepatoblasts to cholangiocyte precursors but promotes maturation of the primitive ductal structures to mature bile ducts. This phenotype is similar to that obtained upon inactivation of Notch signaling in the liver. We tested the hypothesis of a functional overlap between the LKB1 and Notch pathways by gene expression profiling of livers deficient in Lkb1 or in the Notch mediator RbpJκ and identified a mutual cross-talk between LKB1 and Notch signaling. In vitro experiments confirmed that Notch activity was deficient upon LKB1 loss.

Conclusion: LKB1 and Notch share a common genetic program in the liver, and regulate bile duct morphogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145400PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687046PMC
July 2016

AMPK potentiation by LKB1 isoforms.

Oncotarget 2015 Nov;6(34):35139-40

Institut Albert Bonniot, CRI INSERM/UJF U823 Université Grenoble Alpes, Grenoble, France.

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http://dx.doi.org/10.18632/oncotarget.6127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742087PMC
November 2015

Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth.

Nat Cell Biol 2015 Aug 27;17(8):1062-73. Epub 2015 Jul 27.

1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France.

Here, we show that autophagy is activated in the intestinal epithelium in murine and human colorectal cancer and that the conditional inactivation of Atg7 in intestinal epithelial cells inhibits the formation of pre-cancerous lesions in Apc(+/-) mice by enhancing anti-tumour responses. The antibody-mediated depletion of CD8(+) T cells showed that these cells are essential for the anti-tumoral responses mediated by the inhibition of autophagy. We show that Atg7 deficiency leads to intestinal dysbiosis and that the microbiota is required for anticancer responses. In addition, Atg7 deficiency resulted in a stress response accompanied by metabolic defects, AMPK activation and p53-mediated cell-cycle arrest in tumour cells but not in normal tissue. This study reveals that the inhibition of autophagy within the epithelium may prevent the development and progression of colorectal cancer in genetically predisposed patients.
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http://dx.doi.org/10.1038/ncb3206DOI Listing
August 2015

Antitumour activity of an inhibitor of miR-34a in liver cancer with β-catenin-mutations.

Gut 2016 06 19;65(6):1024-34. Epub 2015 Mar 19.

Inserm, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Equipe labellisée LNCC, Paris, France.

Objective: Hepatocellular carcinoma (HCC) is the most prevalent primary tumour of the liver. About a third of these tumours presents activating mutations of the β-catenin gene. The molecular pathogenesis of HCC has been elucidated, but mortality remains high, and new therapeutic approaches, including treatments based on microRNAs, are required. We aimed to identify candidate microRNAs, regulated by β-catenin, potentially involved in liver tumorigenesis.

Design: We used a mouse model, in which β-catenin signalling was overactivated exclusively in the liver by the tamoxifen-inducible and Cre-Lox-mediated inactivation of the Apc gene. This model develops tumours with properties similar to human HCC.

Results: We found that miR-34a was regulated by β-catenin, and significantly induced by the overactivation of β-catenin signalling in mouse tumours and in patients with HCC. An inhibitor of miR-34a (locked nucleic acid, LNA-34a) exerted antiproliferative activity in primary cultures of hepatocyte. This inhibition of proliferation was associated with a decrease in cyclin D1 levels, orchestrated principally by HNF-4α, a target of miR-34a considered to act as a tumour suppressor in the liver. In vivo, LNA-34a approximately halved progression rates for tumours displaying β-catenin activation together with an activation of caspases 2 and 3.

Conclusions: This work demonstrates the key oncogenic role of miR-34a in liver tumours with β-catenin gene mutations. We suggest that patients diagnosed with HCC with β-catenin mutations could be treated with an inhibitor of miR-34a. The potential value of this strategy lies in the modulation of the tumour suppressor HNF-4α, which targets cyclin D1, and the induction of a proapoptotic programme.
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http://dx.doi.org/10.1136/gutjnl-2014-308969DOI Listing
June 2016

Non-cell autonomous effects of targeting inducible PGE2 synthesis during inflammation-associated colon carcinogenesis.

Carcinogenesis 2015 Apr 29;36(4):478-86. Epub 2015 Jan 29.

Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT, USA, Inserm, U1016, département endocrinologie métabolisme et cancer, Institut Cochin, Paris, France and The University of Arizona Cancer Center, Department of Molecular and Cell Biology, Department of Nutritional Sciences, University of Arizona, Tucson, AZ, USA. Tucson, AZ, USA

Microsomal PGE2 synthase-1 (mPGES-1), the terminal enzyme in the formation of inducible PGE2, represents a potential target for cancer chemoprevention. We have previously shown that genetic abrogation of mPGES-1 significantly suppresses tumorigenesis in two preclinical models of intestinal cancer. In this study, we examined the role of mPGES-1 during colon tumorigenesis in the presence of dextran sulfate sodium (DSS)-induced inflammatory microenvironment. Using Apc (Δ14/+) in which the mPGES-1 gene is either wild-type (D14:WT) or deleted (D14:KO), we report that mPGES-1 deficiency enhances sensitivity to acute mucosal injury. As a result of the increased epithelial damage, protection against adenoma formation is unexpectedly compromised in the D14:KO mice. Examining the DSS-induced acute injury, cryptal structures are formed within inflamed areas of colonic mucosa of both genotypes that display the hallmarks of early neoplasia. When acute epithelial injury is balanced by titration of DSS exposures, however, these small cryptal lesions progress rapidly to adenomas in the D14:WT mice. Given that mPGES-1 is highly expressed within the intestinal stroma under the inflammatory conditions of DSS-induced ulceration, we propose a complex and dual role for inducible PGE2 synthesis within the colonic mucosa. Our data suggest that inducible PGE2 is critical for the maintenance of an intact colonic epithelial barrier, while promoting epithelial regeneration. This function is exploited during neoplastic transformation in Apc (Δ14/+) mice as PGE2 contributes to the growth and expansion of the early initiated cryptal structures. Taken together, inducible PGE2 plays a complex role in inflammation-associated cancers that requires further analysis. Inducible PGE2 production by mPGES-1 is critical for the colonic mucosal homeostasis. This function is exploited in the presence of the neoplastic transformation in Apc (Δ14/+) mice as PGE2 contributes to the growth and expansion of the early cryptal structures.
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http://dx.doi.org/10.1093/carcin/bgv004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392604PMC
April 2015

T-cell factor 4 and β-catenin chromatin occupancies pattern zonal liver metabolism in mice.

Hepatology 2014 Jun 14;59(6):2344-57. Epub 2014 Apr 14.

Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1016, Paris, France.

Unlabelled: β-catenin signaling can be both a physiological and oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20%-40% of hepatocellular carcinomas (HCCs) with specific metabolic features. We decipher the molecular determinants of β-catenin-dependent zonal transcription using mice with β-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by T-cell factor (Tcf)-4 and β-catenin, transcriptome, and metabolome. We find that Tcf-4 DNA bindings depend on β-catenin. Tcf-4/β-catenin binds Wnt-responsive elements preferentially around β-catenin-induced genes. In contrast, genes repressed by β-catenin bind Tcf-4 on hepatocyte nuclear factor 4 (Hnf-4)-responsive elements. β-Catenin, Tcf-4, and Hnf-4α interact, dictating β-catenin transcription, which is antagonistic to that elicited by Hnf-4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by β-catenin, partly through xenobiotic nuclear receptors.

Conclusions: β-catenin patterns the zonal liver together with Tcf-4, Hnf-4α, and xenobiotic nuclear receptors. This network represses lipid metabolism and exacerbates glutamine, drug, and bile metabolism, mirroring HCCs with β-catenin mutational activation.
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http://dx.doi.org/10.1002/hep.26924DOI Listing
June 2014

General mechanisms of cancer cell metabolic adaptation.

Authors:
Christine Perret

Ann Endocrinol (Paris) 2013 May 6;74(2):69-70. Epub 2013 Apr 6.

Inserm U1016, département endocrinologie métabolisme et cancer, institut Cochin, université Paris Descartes, 24, rue du Faubourg-Saint-Jacques, 75014 Paris, France.

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http://dx.doi.org/10.1016/j.ando.2013.02.001DOI Listing
May 2013

The tumor suppressor Apc controls planar cell polarities central to gut homeostasis.

J Cell Biol 2012 Aug 30;198(3):331-41. Epub 2012 Jul 30.

Laboratoire de Biophotonique et Pharmacologie, Unité Mixte de Recherche 7213, Centre National de la Recherche Scientifique, 67401 Illkirch, France.

The stem cells (SCs) at the bottom of intestinal crypts tightly contact niche-supporting cells and fuel the extraordinary tissue renewal of intestinal epithelia. Their fate is regulated stochastically by populational asymmetry, yet whether asymmetrical fate as a mode of SC division is relevant and whether the SC niche contains committed progenitors of the specialized cell types are under debate. We demonstrate spindle alignments and planar cell polarities, which form a novel functional unit that, in SCs, can yield daughter cell anisotropic movement away from niche-supporting cells. We propose that this contributes to SC homeostasis. Importantly, we demonstrate that some SC divisions are asymmetric with respect to cell fate and provide data suggesting that, in some SCs, mNumb displays asymmetric segregation. Some of these processes were altered in apparently normal crypts and microadenomas of mice carrying germline Apc mutations, shedding new light on the first stages of progression toward colorectal cancer.
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http://dx.doi.org/10.1083/jcb.201204086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413367PMC
August 2012

The four and a half LIM-only protein 2 regulates liver homeostasis and contributes to carcinogenesis.

J Hepatol 2012 Nov 11;57(5):1029-36. Epub 2012 Jul 11.

Institut Pasteur, Unité d'Oncogenèse et Virologie Moléculaire, France.

Background & Aims: The four and a half LIM-only protein 2 (FHL2) is upregulated in diverse pathological conditions. Here, we analyzed the effects of FHL2 overexpression in the liver of FHL2 transgenic mice (Apo-FHL2).

Methods: We first examined cell proliferation and apoptosis in Apo-FHL2 livers and performed partial hepatectomy to investigate high FHL2 expression in liver regeneration. Expression of FHL2 was then analyzed by real time PCR in human hepatocellular carcinoma and adjacent non-tumorous livers. Finally, the role of FHL2 in hepatocarcinogenesis was assessed using Apo-FHL2;Apc(lox/lox) mice.

Results: Six-fold increase in cell proliferation in transgenic livers was associated with concomitant apoptosis, resulting in normal liver mass. In Apo-FHL2 livers, both cyclin D1 and p53 were markedly increased. Evidence supporting a p53-dependent cell death mechanism was provided by the findings that FHL2 bound to and activated the p53 promoter, and that a dominant negative p53 mutant compromised FHL2-induced apoptosis in hepatic cells. Following partial hepatectomy in Apo-FHL2 mice, hepatocytes displayed advanced G1 phase entry and DNA synthesis leading to accelerated liver weight restoration. Interestingly, FHL2 upregulation in human liver specimens showed significant association with increasing inflammation score and cirrhosis. Finally, while Apo-FHL2 mice developed no tumors, the FHL2 transgene enhanced hepatocarcinogenesis induced by liver-specific deletion of the adenomatous polyposis coli gene and aberrant Wnt/β-catenin signaling in Apc(lox/lox) animals.

Conclusions: Our results implicate FHL2 in the regulation of signaling pathways that couple proliferation and cell death machineries, and underscore the important role of FHL2 in liver homeostasis and carcinogenesis.
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http://dx.doi.org/10.1016/j.jhep.2012.06.035DOI Listing
November 2012

Combined hepatocellular-cholangiocarcinomas exhibit progenitor features and activation of Wnt and TGFβ signaling pathways.

Carcinogenesis 2012 Sep 13;33(9):1791-6. Epub 2012 Jun 13.

INSERM, UMR991, Université de Rennes 1, Liver Metabolisms and Cancer Rennes, France.

Intrahepatic malignant tumours include hepatocellular carcinomas (HCC), cholangiocarcinomas (CC) and combined hepatocholangiocarcinomas (cHCC-CC), a group of rare and poorly characterized tumours that exhibit both biliary and hepatocytic differentiation. The aim of the study was to characterize the molecular pathways specifically associated with cHCC-CC pathogenesis. We performed a genome-wide transcriptional analysis of 20 histologically defined cHCC-CC and compared them with a series of typical HCC and of CC. Data were analysed by gene set enrichment and integrative genomics and results were further validated in situ by tissue microarray using an independent series of 152 tumours. We report that cHCC-CC exhibit stem/progenitor features, a down-regulation of the hepatocyte differentiation program and a commitment to the biliary lineage. TGFβ and Wnt/β-catenin were identified as the two major signalling pathways activated in cHCC-CC. A β-catenin signature distinct from that observed in well-differentiated HCC with mutant β-catenin was found in cHCC-CC. This signature was associated with microenvironment remodelling and TGFβ activation. Furthermore, integrative genomics revealed that cHCC-CC share characteristics of poorly differentiated HCC with stem cell traits and poor prognosis. The common traits displayed by CC, cHCC-CC and some HCC suggest that these tumours could originate from stem/progenitor cell(s) and raised the hypothesis of a potential continuum between intrahepatic CC, cHCC-CC and poorly differentiated HCC.
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http://dx.doi.org/10.1093/carcin/bgs208DOI Listing
September 2012

[NKT cells in the liver environment interact with Wnt/β-catenin and promote the emergence of liver carcinoma].

Med Sci (Paris) 2012 May 30;28(5):473-5. Epub 2012 May 30.

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http://dx.doi.org/10.1051/medsci/2012285010DOI Listing
May 2012

Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1).

Proc Natl Acad Sci U S A 2012 Jun 14;109(23):8965-70. Epub 2012 May 14.

Institut Cochin, Department of Endocrinology, Metabolism and Cancer, Université Paris Descartes, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, 75014 Paris, France.

Intestinal epithelium has the capacity to self-renew and generate differentiated cells through the existence of two types of epithelial stem cells: active crypt base columnar cells (CBCs) and quiescent +4 cells. The behaviors of these cells are regulated both by intrinsic programs and by extrinsic signals sent by neighboring cells, which define the niche. It is clear that the β-catenin pathway acts as an essential intrinsic signal for the maintenance and proliferation of CBC, and it was recently proposed that Paneth cells provide a crucial niche by secreting Wingless/Int (Wnt) ligands. Here, we examined the effect of disrupting the intestinal stem cell niche by inducible deletion of the transcription factor Math1 (Atoh1), an essential driver of secretory cell differentiation. We found that complete loss of Paneth cells attributable to Math1 deficiency did not perturb the crypt architecture and allowed the maintenance and proliferation of CBCs. Indeed, Math1-deficient crypt cells tolerated in vivo Paneth cell loss and maintained active β-catenin signaling but could not grow ex vivo without exogenous Wnt, implying that, in vivo, underlying mucosal cells act as potential niche. Upon irradiation, Math1-deficient crypt cells regenerated and CBCs continued cycling. Finally, CBC stem cells deficient in adenomatous polyposis coli (Apc) and Math1 were able to promote intestinal tumorigenesis. We conclude that in vivo, Math1-deficient crypts counteract the absence of Paneth cell-derived Wnts and prevent CBC stem cell exhaustion.
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http://dx.doi.org/10.1073/pnas.1201652109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384132PMC
June 2012